Poorly soluble drugs are often associated with low and variable bioavailability. To achieve the desired therapeutic levels in the blood, poorly soluble drugs need to be administered at higher dose and some drugs need to be administered with food.
Isotretinoin is an orally active retinoic acid derivative for the treatment of severe refractory nodulocystic acne. Peak plasma concentrations of Isotretinoin were reported to vary widely among individuals, but usually occur 2 to 4 hours after administration. Steady-state concentrations were also subject to considerable inter-individual variation. After multiple dosing, the major systemic metabolite of isotretinoin in man is 4-oxo-isotretinoin, and its plasma concentration is about 4-fold higher than that of the parent drug. The elimination half-life of isotretinoin has been reported as about 10 to 20 hours in several studies in healthy subjects or patients (Ward A et. al Drugs. 1984; 28(1):6-37).
Solubility and permeability are two important parameters that determine the rate and extent to which the drug molecules reach systemic circulation. Drug levels in the blood within a therapeutic window are necessary to achieve the therapeutic benefit of the molecule. Poor and variable bioavailability may lead to a poor therapeutic outcome and reduced patient compliance. Repeated dosing and meal restrictions also contribute to increased patient complaints.
Apart from solubility, poor permeability, extensive first pass metabolism and drug efflux mechanism also contribute to poor bioavailability. Formulating poorly soluble drugs in a lipid-based composition may also improve permeability and reduce metabolism and efflux presumably via alternative lymphatic uptake. The present invention addresses this need.